Heat Substrate and/or Image Enhancement Compositions and Enhanced Tissue Ablation Methods

ABSTRACT

Ferritin or iron-based image enhancement agents identify target tissue for treatment or ablation and are heated by microwave absorption. Microwave heat substrates enhance microwave hyperthermal ablation treatment, and may be percutaneously delivered and imaged by x-ray CT during placement of the microwave treatment antenna, allowing more precise positioning and more complete ablation of a tumor site. One method of treating a target tissue uses image-guided delivery of a heat substrate with a reverse-phase change polymer, and may apply energy to fix a mass of the material in the tissue. The fixed polymer may increase hyperthermia, form a thermal boundary, or blockade a vessel or passage so as to reduce or prevent undesired conductive cooling by contiguous tissue, or may deliver a localized treatment drug at the site, upon heating or as it degrades over time.

RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/831,615, filed Dec. 5, 2017, which is a continuation of internationalapplication No. PCT/US2016/035995, filed on Jun. 6, 2016, which isrelated to and claims the priority of U.S. Provisional Application No.62/171,609, filed on Jun. 5, 2015. Each of these applications, togetherwith its drawings, appendices and attachments is hereby incorporatedherein by reference in its entirety.

TECHNICAL FIELD

The present invention relates to nanoparticle-based theranostic methodsof imaging and/or treating tissue, such as a tumor or cancerous tissuepresent in a gland or organ. It also relates to image-guided minimallyinvasive treatments of such tissue, such as intravascular embolicablation treatment.

BACKGROUND

Much medical imaging involves imaging modalities that have beendeveloped for gross anatomical applications, such as the detection ofinternal traumatic events (such as bone fractures or dislocations) bytransmission x-ray imaging, or such as detection of soft tissuepathologies by magnetic resonance imaging (MRI) or x-ray computedtomography (CT). In general, x-ray imaging is poorly adapted todiscriminating soft tissue features due to the low absorbance of suchtissue and the concomitant low level of image contrast, as compared tothe high contrast x-ray images produced, for example, by mineralizedskeletal features, which have higher absorbance and thus appear withhigh x-ray contrast, MRI, which depends upon stimulation of magneticdipoles of underlying molecules and upon detection of signals emitted bythe stimulated tissue, is better suited to soft tissue imaging, and canprovide tomographic reconstructions of diverse internal soft tissues,organs and other features. Various image enhancement formulations havebeen developed to further enhance MRI detection of many specific typesof tissue or defects therein, for example, to image blood flow, or todetect vessel leaks in the brain.

Recently, much research has been carried out to develop imageenhancement agents that will specifically accumulate at and attach to atarget feature of interest, such as a liver cancer, so as to render thetarget feature visible by medical imaging. For example an MRIenhancement agent for parenteral delivery may include nanoparticles, abiocompatible coating and a monoclonal antibody (mAB) that binds thenanoparticle agent to a receptor or a peptide present on or expressed bya specific tumor cell line, so that as the agent circulates itpreferentially binds to and accumulates at the target tissue, and thusenables MRI screening for and early detection of such tumors. For someimaging agents based upon nanoparticles, there have been proposals thatthe nanoparticle further carry a chemotherapeutic treatment cargo, or beengineered to release a toxic residue, and be delivered in a form thatcan be released at the tissue binding site via application ofexternally-applied stimulation, such as ultrasonic or electromagneticstimulation. By using such targeted nanoparticles one can therebyselectively increase the concentration which resides at the intendedtreatment site, in contact with cancer cells; one can visually confirmboth the existence of the type of targeted tissue and confirm theeffective delivery of agent at the site, thereby assuring that the chemocargo directly contacts the specific tissue requiring treatment. See,for example International Application WO 2014/031727 published 27 Feb.2014, which reports a tissue-targeting engineered ferritin for MRIimaging that is specifically taken up by targeted cells to enablediagnostic imaging, and may be externally stimulated to release a largequantity of toxic iron ions and treat the targeted tissue. That ferritininvolves a genetically-engineered ferritin cage derived fromArchaeoglobus Fulgidus developed by Swift and Sana, as further describedin the aforesaid international application.

However, the amount of material that may be carried by nanoparticles todeliver as a treatment agent, or the concentration of nanoparticles thatwill be result at a tissue site (either for treatment purposes or forimage enhancement purposes) may be quite small. Actual binding maydepend upon a number of potentially competitive factors, including suchfactors as the binding specificity, and the rates of cellular uptake orof diffusion, degradation and/or clearance of the agent. When magneticnanoparticles are to be externally stimulated to heat the contactedtissue, the size, coatings, contents and other aspects of the materialwhich has been optimized in preparing a nanoparticle-based or otherimaging agent may limit the amount of energy that can be locallyimparted to or transferred by the agent to the tissue site. Moreover,when electromagnetic stimulation is intended to result in hyperthermia,the level of conductive cooling by the surrounding thermal mass orcooling provided by blood circulation may be so large as to effectivelyprevent energized nanoparticles from increasing the temperature of thetargeted tissue features to the necessary ablation threshold, or mayrequire a massive or high-powered magnetic field generator and verytechnical positioning or adjustment to attain sufficiently elevatedlocal temperatures. Similar factors may strongly limit the achievablelevel of therapy when the operative mechanism involves stimulating theagent to release material or stimulating the agent to itself locallyinteract with tissue. One article has reported investigating the use ofiron oxide nanoparticles as an accelerant for microwave ablation, butwas unsuccessful in a comparison study with RF and magnetichyperthermia. Isfort et al, Cardiovasc Intervent Radil (2014) DOI10.1007/s00270-013-0832-7.

It would therefore be desirable to provide a tumor-targeting or imageenhancing agent that enables, simplifies, enhances or provides atherapeutic activity.

It would also be desirable to provide an agent that is simple todeliver, free of toxicity, and effective to simplify or improve localtreatment, such as microwave or other hyperthermal ablation treatment,of a targeted tumor or tissue pathology.

It would also be desirable to provide simpler, safer or improved methodsfor treatment of a targeted tumor or tissue pathology, such as thermalor microwave tissue ablation methods.

SUMMARY

These and other desirable improvements are achieved with improvedmaterials and methods of the invention as described further below.

The present invention provides enhanced methods of treating tissue, suchas a tumor or cancerous tissue present in tissue, a gland or organ, andoperates by providing a heat substrate component or material which maybe heated by applying electromagnetic or microwave energy to locallyablate tissue. In various embodiments the invention also provides imageenhancement, enhancing visibility of a targeted tissue or feature by CTor MR imaging modalities, and/or allowing image guided delivery of thesubstrate for treatment. The imaging agent may be adapted to targetspecific tissues or characteristics of a tumor so as to detect andidentify a tumor or early stage cancer and thereby confirm presence ofthe agent at the tissue site. In embodiments wherein the heat substrateis also an image enhancing agent, it may be externally heatable toenhance thermal ablation of the targeted tissue, for example, to renderfaster, or more localized or otherwise more effective microwave ablationor electromagnetically stimulated heating of the tissue that has beenspecifically targeted or contacted by the agent.

In one aspect of the invention, an engineered ferritin is targeted tospecific tissues by binding specific ligands to an outer surface of theferritin cage, and acts as an MRI contrast agent to provide positiveidentification of the target tissues in which the agent has accumulated.The resultant presence of a high iron concentration enhances theefficacy, e.g., rate of temperature increase, of a microwave ablationprocedure, providing an additional capability for such ferritin materialto define a treatment region and also reduce damage to surroundingtissue.

In another or further embodiment for enhanced thermal tissue ablation, aheat substrate agent is formulated for direct delivery, for exampleimage-guided delivery by catheter or needle, and includes a reversephase change carrier gel or polymer that thickens as its temperature isincreased, or that solidifies at or near body temperature, fixing thesubstrate and/or hardening the polymer at the delivery site. Wheninjected into a passage such as a duct or the arterial tree of a targettissue mass, solidification blocks the passage, closing off circulatorycooling and thereby lowering the effective thermal mass of the targettissue, and increasing the effective rate or endpoint of tissue heatingin the mass as a whole. Solidification may be assured by providing areverse phase change material that solidifies at body temperature;alternatively, solidification may also be accelerated by applying energyto the heat substrate to quickly reach the transition temperature. Thereverse phase change polymer advantageously enables a treatment modality(such as magnetic excitation to heat a nanoparticle agent) which mightotherwise be ineffective at transferring sufficient heat to raise thecontacted tissue to an ablation level in the local area. For certaintissue structures, rather than blocking ducts or vessels, the heatablereverse phase change polymer may also be delivered to surround andenclose a tissue target in a heat sheath, or to install a boundingthermal wall of material that overcomes or limits the amount ofundesired conductive cooling that would otherwise occur. At highertemperatures the polymer can solidify and expel therapy agents into thecontiguous tissue or tissue structure, or release a therapeutic agent atthe target site over an extended time as the material breaks down.

In various embodiments, heating of the heat substrate may beaccomplished by externally applying an alternating electromagnetic field(for example to heat a substrate, such as a ferritin-based or other ironoxide-based treatment or imaging agent containing iron or Fe₃O₄) orheating may be effected by applying microwave energy to the treatment orimaging agent. The presence of iron (as engineered ferritinnanoparticles providing enhanced contrast effect for imaging, or asferumoxytol for iron replacement therapy) enhances the tissue heatingand thus the tissue sensitivity to microwave heating, or heating byelectromagnetic stimulation. Targeted MRI image enhancement to identifyspecific tissue sites may be effected using iron-laden engineeredferritin nanoparticles carrying monoclonal antibodies to bind to sitesof the specific targeted tissue, or sites may be marked by image-guidedelivery of an agent such as the iron-replacement agent ferumoxytol tothe intended site. As noted above, the ferritin or ferumoxytol may alsoserve as heat substrate for thermal tissue ablation. The reverse-phasetransition polymer need not itself include image-enhancing components,but may be placed by image-guided delivery and then independently heatedto quickly block circulation or immobilize the material at the site oncethe target has been identified.

Unlike chemotherapy injections which can diffuse away from the site ofinjection the iron nanoparticle/polymer becomes a gel and thus localizesto where it is injected. The iron oxide matrix within the gel can bedose dependently heated to the cytotoxic threshold via interstitial orextracorporeal excitation by a radiofrequency field (e.g microwave). Theiron oxide/gel combination may also act as a contrast agent allowing forimage-guided delivery and verification of the volume occupied by thegel.

Existing thermal ablation techniques used to treat cancerous tumors havea high local recurrence rate (˜40%) which is, in part due to the coolingeffect of blood vessels. Blocking the blood vessels with the ironnanoparticle/polymer will achieve two purposes: reducing tumor bloodflow (thus mitigating any cooling effects of flowing blood) and allowinglocalized thermal energy delivery through the excitation of the localiron oxide within the polymer, via interstitial or extracorporealexcitation. Current liver tumor directed therapies through the arterialtree rely on chemotherapy emulsions, drug-eluting beads or radioactivebeads that are expensive and only rely on the toxic effects of the drugor the ionizing radiation. The iron oxide nanoparticle/polymer of thepresent invention is a more cost effective formulation and has a highersafety profile because the components are readily broken down andmetabolized within a few weeks.

The inventors have further identified a non-iron agent useful as a heatsubstrate that both imageable and effective for microwave thermalablation, namely cesium chloride (CsCl). This heat substrate may beadded to the agent or to a reverse-phase transition polymer as aningredient to substantially accelerate heating and solidification of thepolymer, or may be delivered to the tissue itself to enhance heating andablation of the tissue using a percutaneously placed microwave antenna.The CsCl material is also CT imageable, and thus supports additionalimage-guided microwave therapies.

Various other agents may be used to enhance ablation by increasing thecoefficient of microwave absorption, allowing faster heating, lowerpower, and more effective tumor ablation via minimally invasiveprocedures using a conventional microwave surgical instrument. Inembodiments of the invention and methods of treatment, the targetingagent, the polymer heating agent, and the tumor sensitizing agent may bedifferent materials, and their size, form, concentration or otherattributes may be individually optimized for different properties, suchas (1) targeting and imaging the tumor by CT or MRI; (2) placing andquickly heating, by electromagnetic or microwave stimulation, theblocking gel to a solid state to reduce circulatory cooling of theimaged tumor; and (3) heating the tumor-bound or tumor-binding agentsufficiently to ablate the tissue to which the targeted agent is fixed.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other features of the invention will be understood from thedrawings and the description herein, taken together with the above-citedinternational Application WO 2014/031727 published 27 Feb. 2014 which ishereby incorporated herein in its entirety by reference. The drawings,description, cited peers and claims, infra, describe methods andmaterials of the invention and intended variations and extensionsthereof, together with certain representative and proof-of-principlemeasurements and experiments, wherein

FIG. 1 is graph of temperature increases observed with several heatsubstrate agents using low power microwave stimulation;

FIG. 2 is a chart showing effective temperature and heating profileswith several iron-based formulations, CsCl concentrations and polymer invitro; and

FIGS. 3A, 3B and 3C illustrate CT imaging characteristics of a cesiumchloride heat substrate revealing its dual utility for microwave beatingand x-ray imaging.

DETAILED DESCRIPTION

The invention may be viewed as an advance in image-guided thermalablation (IGTA), a conventional treatment which uses needle-likeapplicators to deliver energy into tumors and cause instantaneous celldeath. Aspects of the invention also promise improved ablation orheating characteristics for treating tumors or isolated metastatictissue portions that have been targeted with imageable theranosticpreparations, such as image enhancement preparations containingmAB-targeted ferritin nanoparticles as described in the aforementionedInternational Application WO 2014/031727 and technical papers referencedtherein. Some embodiments involve heat-mediated release of a treatmentagent. A central discovery behind the improved tissue ablationprocedures and materials described herein is the realization thatiron-loaded imaging agents and theranostic preparations such as theaforesaid ferritin or iron oxide preparations arc efficient absorbers ofmicrowave radiation, and may be employed for, or further enhanced forcarrying out, processes of microwave hyperthermal ablation, localizedfixation and drug delivery, and also enhanced imaging of treatmentprocesses.

FIG. 1 illustrates microwave heating and heat transfer characteristicsof several iron-based formulations, as well as the non-iron materialcesium chloride which is identified herein as an effective and usefulmicrowave-absorbing heat substrate, and polymer formulations.

Microwave heating was carried out using a 15 watt 0.915 gigaherzmicrowave source directed at a vial of each preparation, and theresulting temperature rise was plotted over the course of approximatelysix minutes. Increasing concentrations of cesium chloride in waterresulted in increased heating; similar microwave heating characteristicsare expected for cesium iodide.

FIG. 2 is a Table summarizing the effective heating and endpointsachieved with various concentrations of the indicated materials in smallsample vials located in a beaker of soft agar. The beaker provides aconsistent external temperature surround so as to closely model expectedheat transfer and temperature increase profiles that would be expectedin the body under the applied levels of microwave heating. The microwaveenergy was 15 W for all but the first sample, for which various powerlevels were applied to assess heating of a plain water control, and forall samples was a 915 MHz microwave signal, which was applied with acoaxial dipole antenna of construction similar to that used for clinicaltherapy, e.g., a needle-like microwave applicator. Ferritin, the ironoxide formulation Ferumoxytol and polymer each displayed usefulmicrowave heating characteristics, and cesium chloride solutionsachieved higher temperature increases, while cesium chloride in polymerresulted in such a fast temperature rise that it needed to be shut offbefore an explosion could occur. These tests established that theiron-based agents, in addition to the polymer, possessed suitablemicrowave absorption characteristics, so that the imaging agents couldalso be used for microwave hyperthermal ablation of the imaged tissue.The tests also established that addition of cesium chloride in suitableconcentrations would enhance the ablation efficacy.

It was further determined that CsCl in relevant concentrations is itselfreadily imaged in CT devices. Small vials of distilled water and ofvarious concentrations of CsCl were placed in a jig as shown in FIG. 3Aand imaged with a GE Optima 580 W CT scanner, using a brain CT protocol:120 kV, 50 mA, 0.8 second rotation, 0.562 pitch and 16x.625 detectorconfiguration. The radiation output (CTDIvol) was 12.08 mGy, Dose LengthProduct was 193.88 mGy-cm. The images were evaluated to determine theradiodensity in Hounsfield units. FIGS. 3B and 3C display theradiographic images and the radiodensities, establishing that a range ofsalt concentrations are suitable for x-ray imaging. Thus cesium chloride(as well as cesium iodide) can be both an effective microwave heatsubstrate as well as an x-ray CT contrast agent.

Thus for the methods claimed herein, the cesium salt may be imaged byCT, and heated by microwave energy, and the iron-based heat substratematerials may be imaged by MRI or other means, and heated by applyingelectromagnetic or microwave energy. These properties advantageously areapplied herein to provide enhanced imaging and treatment protocols.

FIGS. 3A-3C thus illustrate effective CT imaging of variousconcentrations of CsCl solution, demonstrating suitability of thismaterial for the heat substrate compositions and image-guided thermalablation methods described herein.

Image guided thermal ablation (IGTA) is a safe, low-cost, minimallyinvasive method that can treat numerous tumor types, and is often analternative to surgical resection. However, while IGTA is effective forlocal treatment and palliation of symptoms, high treatment variabilitymay be expected when targeting heterogeneous tissue and tumor types, andraises concerns. The present invention instead uses a drug-devicecombination to improve local control such as localization andeffectiveness of heating and, in some embodiments, more effective orprecise delivery to a tumor site, so as to improve patient outcomes andbroaden the utility of such directed thermal therapy. Specifically,rather than the conventional use of ultrasound to position a microwaveablation antenna, the heat substrates and imaging agents describedherein further enable CT imaging of percutaneous microwave ablationprocedures and enhanced hyperthermic response of the identified tissuesites.

One further aspect of the invention may utilize the local tissue heatingeffects of electromagnetic or microwave treatments by reducing bloodflow, by means of arterial blockade in the treated orthermally-communicating/proximate tissue. Blockade may be effectivelyachieved in a thermal ablation methodology that employs a polymer and aheat substrate. The term heat substrate herein refers to a material thatmay be heated in situ by an applied field, such as an alternating magnetfield of suitable strength and frequency, or such as a microwave field(which may be applied with a conventional microwave ablation setup orhand piece—e.g, a needle-like antenna).

As described above, these heat substrates may include ironoxide-nanoparticle material (Fe₃O₄-Np, e.g., ferumoxytol or anengineered ferritin.) which in certain embodiments may be presented inan imaging enhancement agent and/or a treatment agent. Heat substratesmay alternatively include other materials that have high efficiency forabsorbing the applied energy, e.g., microwave or electromagneticradiofrequency field, and generating heat. As described above, cesiumchloride has been found to substantially accelerate heating under low(15 W) applied microwave power, and also to provide CT contrast, and isthus another suitable heat substrate that provides imageability as wellas improved heating during microwave ablation.

In addition to augmentation by blockade, local tissue heating effectsmay in some embodiments also be achieved by placing polymer/ferumoxytolor engineered ferritin nanoparticles into tumors percutaneously,intraductally, or intravenously with specific antibody-targeteddelivery. Further enhancements are achieved by combining these heatsubstrate components with a biodegradable reverse-phase transitionpolymer, to operate as an embolization medium or a localfixation/delivery mechanism. Once injected, the solution becomesgel-like and heats via a non-invasive, extracorporeal, or interstitialapplied energy field. The methodology targets an exact ablation volumeand provides a controllable, uniform ablation temperature. Unlikechemotherapy, which can diffuse from the injection site, the heatsubstrate/polymer localizes to the site. The iron oxide/gel combination,or CsCl/gel also acts as an imaging or contrast agent, allowing forimage-guided delivery and verification of the volume occupied by thegel, and these are expected to be highly cost effective and safer thanprior treatment protocols not involving blockade because components aremetabolized within weeks.

Several points of innovation merit specific mention. First, thecombination of heat substrate and polymer creates a suspension where theapplied external electromagnetic field or percutaneous microwave fieldheats the material uniformly. Second, the biphasic polymer becomesgelatinous at body temperature and localizes at the injection point.Third, the polymer may be one that solidifies and expels liquid attemperatures consistent with ablation procedures. Fourth, thepolymer/heat substrate combination is viewable under magnetic resonanceimaging or CT imaging so localization can be verified prior toelectromagnetic or microwave excitation. Finally, the polymer withappropriate characteristics may be one such as a block-co-polymerconsisting of polyethylene glycol, which is covalently esterified by anFDA-approved poly lactic-co-glycolic acid on both ends. For ferumoxytolas the iron-based heat substrate, a standard dose is two intravenousadministrations of 510 mg (Fe content) over eight days. For thisapplication, ferumoxytol (5-10 mg, Fe content), currently used to treatiron deficiency anemia in adult patients with chronic kidney disease,may be dissolved in the polymer solution (<100 μL) per tumor volume (<1cm³), which is 50 to 100 times less than a clinical dose. The heatsubstrate being trapped in a gel that slowly releases the iron oxide,mitigates or effectively reduces the risk of arty significant toxicity,thus providing low-dose but highly effective treatment.

The improved tissue imaging and localized tissue heating of theinvention should provide better treatment for hepatocellular and othercarcinomas. Hepatocellular carcinoma is the fifth most common malignancyworldwide. In addition, the liver is the most common metastatic site ofcolorectal cancer: the second most common cause of cancer-related deathsin the United States. Current liver-directed therapies have been largelyapplied as palliative measures—some at high cost—with high recurrencerates. If hepatic disease burden were to be lessened by this less toxicand more cost-effective means, patient costs should be reducedsubstantially. Thus, Fe₃O₄-Np block co-polymer, or CsCl reverse phasechange polymer blockade by image-guided delivery, both have greattreatment potential in this large group of patients.

Methods of the invention employ an electromagnetic (EM) field ormicrowave source as the energy source and a combination of ferumoxytol(Fe₃O₄-Np) or CsCl, and a biodegradable reverse-phase transition polymersolution as a heat substrate for blockade. The polymer solution is aliquid at ambient temperature, but a gel at typical body temperature (35to 37 degrees Celsius). Upon a further increase in temperature, thepolymer precipitates by expelling water molecules from the polymericlattice structure while nanoparticles are still trapped.

This expulsion effect is advantageously utilized in an embodiment of theinvention as a mechanism for delivering a therapy agent from the fixedpolymer/heat substrate body. The Fe₃O₄-nanoparticles (Nps) are coatedwith a poly-carbohydrate molecule (a cross-linked dextran withnon-reducing end, decomposition temperature less than 240 degreesCelsius) so as to be hydrophilic and, thus, miscible with the aqueouspolymer solution. The homogeneous distribution of Fe₃O₄-Np in thepolymer solution permits uniform heating within the target ablationvolume. With image-guidance like CT or MRI, the desired solution volumewith a known Fe₃O₄-Np (or CsCl) concentration is deposited in and aroundthe tumor or other tissue target. Subsequently, the injected polymercontaining Fe₃O₄-Np or CsCl turns into a gel of predetermined ablationshape and volume. Fe₃O₄-Np in the gel may then be heated by anon-invasive EM field produced by an inductive EM generator, orinterstitial microwave energy may be applied to heat the CsCl substrate.The temperature is controlled and ablation optimized by varying severalparameters: duration (minutes), electric current (A), power (kW), andfrequency (kHz), the iron and cesium concentration (mM), and ablationvolume (cm³). The exact iron and cesium concentration of theintra-arterial and directly injected compound, along with the EM fieldand MW parameters to optimize the efficacy of tumor heating, may bedetermined by routine experimental assay, calibration and adjustmentbefore application to patients in vivo.

Historically, transcatheter arterial chemoembolization (TACE) andthermal ablation procedures have been most widely applied tohepatocellular carcinoma patients who are not eligible for surgery.Initial implementation and evaluation of the methodology describedherein may be carried out and efficacy confirmed with TACE, microwaveablation (MWA), and direct intra-tumoral injection using an animalmodel, such as rabbit VX2 liver tumor model. A dose escalation study canidentify the optimal iron concentration in the Fe₃O₄/polymer solutionfor intrarterial and direct injection and the optimal power and timesettings of electromagnetic activation (EMA). After iron concentrationand EMA parameter optimization, live animal studies may be undertakenalong the route to evaluate and qualify the method for clinical use. Foranimal studies, a 3T MRI imaging unit can be used to monitor thedistribution of the Fe₃O₄-Np/polymer solution as well as treatmenteffects within the liver and liver tumors. Histopathologic analysesincluding viability staining would preferably also performed to assessvascular thrombosis, necrosis, and tumor viability.

As described herein the thermal substrate properties of engineeredferritin and other iron-based nanoparticle agents, and the demonstratedcharacteristics of ordinary CsCl as a thermal substrate together withits imageabiliy by several common healthcare imaging systems, amplysupport the efficacy of the improved, low-cost and safe treatmentmethods and image-based diagnostic methods, as well as new usefulcompositions for carrying out the methods described herein. In addition,simple screening methods may quickly identify additional inorganic saltsor small molecules with suitable properties to form heat substratematerials with enhanced safety and heating characteristics. Reference ismade to the U.S. provisional patent application of which priority isclaimed and the appendices thereto, as well as the above mentionedinternational patent application WO 2014/031727, as well as to varioustechnical papers useful for understanding or preparation of photothermaland reverse phase gel or polymer preparations, including the followingpapers: Ninh, C., Cramer, M., Bettinger C J., (2014). Photoresponsivehydrogel networks using melanin nanoparticle photothermal sensitizers.Biomater. Sci., 2, 766-774; Brown D B, Geschwind J F, Soulen M C,Millward S F, Sacks D (2006). “Society of Interventional Radiologyposition statement on chemoembolization of hepatic malignancies”. J VascInterv Radiol 17(2): 217-23; M. Ginsburg, T. Doshi, A. Miller, T.Robbins, R. Kunnavakkam, L. H. Kang, T. VanHa. (2013). Comparisonbetween transarterial chemoembolization in combination withradiofrequency ablation versus microwave ablation in the management ofhepatocellular carcinoma. J Vasc Interv Radiol, 24(4) S43-44; Qian T,Chen M, Gao F, Meng F, Gao X, Yin H. (2014). Diffusion-weighted magneticresonance imaging to evaluate microvascular density after transarterialembolization ablation in a rabbit VX2 liver tumor model. Magn ResonImaging. 32(8);1052-7; Duan X, Zhou G, Zheng C, Liang H, Liang B, SongS, Peng G. (2014). Heat shock protein 70 expression and effect ofcombined transcatheter arterial embolization and radiofrequency ablationin the rabbit VX2 liver tumour model. Clin Radiol. 69(2):186-93; andMostafa E M, Ganguli S, Faintuch S, Mertyna P, Goldberg S N. (2008).Optimal strategies for combining transcatheter arterialchemoembolization and radiofrequency ablation in rabbit VX2 hepatictumors. J Vasc Interv Radiol. 19(12):1740-8. The foregoing documents andpapers are all hereby incorporated herein by reference.

The invention being thus described, variations, and modificationsthereof will occur to those of ordinary skill in the art, and all suchvariations and modifications are considered to be within the scope ofthe invention and the claims appended hereto.

1. A localized therapy drug delivery method comprising: administering toa patient a combination therapy formulation, the combination therapyformulation comprising: a therapy drug; a heat substrate agent; and apolymer, the combination therapy formulation formulated for directdelivery to a target tissue at a target site; and fixing the heatsubstrate agent by hardening the polymer at the target site, wherein:hardening the polymer at the target site comprises heating the heatsubstrate agent with an external energy source to increase thetemperature of the combination therapy formulation substantiallyuniformly beyond a given temperature; and hardening the polymer expelsthe therapy drug agent at the target site to deliver the therapy drugover an extended time.
 2. The method of claim 1, wherein heating theheat substrate agent with an external energy source comprises: applyingmicrowave energy via a percutaneous microwave ablation probe positionedin the vicinity of the target tissue; or applying electromagnetic energyvia applying a magnetic field at the target site.
 3. The method of claim1, wherein the heat substrate agent is a material imageable by x-ray CT.4. The method of claim 1, wherein the polymer comprises a reverse phasechange polymer.
 5. The method of claim 1, wherein: the heat substrateagent enhances microwave energy or electromagnetic energy absorption,such that applying microwave energy or electromagnetic energy to aregion of the target tissue elevates the temperature of the heatsubstrate agent and thermally ablates the target tissue; the heatsubstrate agent exponentially increases microwave of electromagneticheating so as to effectively ablate the target tissue; or the heatsubstrate agent is delivered into or surrounding the target site toelevate temperature forming a thermal boundary thereby enhancingtreatment of the target tissue.
 6. The method of claim 5, wherein theheat substrate agent combined with the reverse change polymer fixes thetherapy drug to the target tissue so as to deliver the therapy drug overtime as the heat substrate agent is degraded in position.
 7. The methodof claim 1, wherein the heat substrate agent comprises at least one of:engineered ferritin; ferumoxitol; CsCl; or CsI.
 8. The method of claim1, wherein the therapy drug comprises a chemotherapeutic, or amonoclonal antibody.
 9. The method of claim 1, wherein: the combinationtherapy formulation is a first combination therapy formulation; andfurther comprising: following fixing the heat substrate agent,administering to the patient a second combination therapy formulation,the second combination therapy formulation comprising: a second therapydrug; a second heat substrate agent; and a second polymer, the secondcombination therapy formulation formulated for direct delivery to thetarget tissue at the target site; and fixing the second heat substrateagent by hardening the second polymer at the target site, wherein:hardening the second polymer at the target site comprises heating thesecond heat substrate agent with an external energy source to increasethe temperature of the second combination therapy formulationsubstantially uniformly beyond a given temperature; and hardening thesecond polymer expels the second therapy drug agent at the target siteto deliver the second therapy drug over an extended time.
 10. Atissue-targeting theranostic method, comprising: administering to apatient a heat substrate disposed in a polymer carrier configured fordirect delivery to a target tissue at a target site; and applyingelectromagnetic energy or microwave energy to increase the temperatureof the heat substrate to enhance hyperthermal ablation of the targettissue.
 11. The theranostic method of claim 10, wherein: the polymer isa first polymer; the electromagnetic energy or microwave energy is afirst electromagnetic energy or a first microwave energy; and furthercomprising: administering to the patient a second polymer comprising atreatment agent configured for direct delivery to the target tissue atthe target site; and applying a second electromagnetic energy or asecond microwave energy to increase the temperature of the secondpolymer to release the treatment agent.
 12. The theranostic method ofclaim 11, wherein the polymer comprises a reverse phase polymer.
 13. Thetheranostic method of claim 11, wherein the treatment agent comprises aniron oxide-nanoparticle material.
 14. The theranostic method of claim13, wherein the iron oxide-nanoparticle material comprises ferumoxytolor an engineered ferritin.
 15. The theranostic method of claim 13,wherein the iron oxide-nanoparticle material comprises a nano-particleformulation of Fe₃O₄.
 16. The theranostic method of claim 15, wherein:the nano-particle formulation of Fe₃O₄ is coated with apoly-carbohydrate molecule; and the poly-carbohydrate molecule is across-linked dextran with a non-reducing end.
 17. The theranostic methodof claim 15, wherein the nano-particle formulation of Fe₃O₄ coated withthe poly-carbohydrate molecule has a decomposition temperature lowerthan 240 degrees Celsius.
 18. A localized therapy drug delivery method,comprising: administering a nanoparticle formulation, the nanoparticleformulation comprising a surface functionalized for tumor- ortissue-specific targeting of a target tissue; and applying anelectromagnetic energy or a microwave energy to increase the temperatureof the surface functionalized nanoparticle formulation by hyperthermalablation of the target tissue.
 19. The drug delivery method of claim 18,wherein the nanoparticle formulation comprises ferumoxytol, anengineered ferritin, or an iron-based nanoparticle formulation thatallows MRI imaging to confirm existence of the target tissue andpresence of an agent at a target site.
 20. The drug delivery method ofclaim 18, further comprising: applying a microwave heat substrate toenhance the hyperthermal ablation of the target tissue.
 21. The drugdelivery method of claim 18, further comprising: contacting the targettissue by image guided catheter delivery of a flowable or a conformableheat substrate composition including a reverse-phase change polymer thatthickens or solidifies at body temperature to thereby fix a mass of theflowable or the conformable heat substrate composition at the targetsite.
 22. The drug delivery method of claim 21, further comprising:applying electromagnetic energy or microwave energy to heat the mass andthereby more effectively achieve hyperthermal ablation of the contactedtarget tissue and/or deliver a drug from the mass to the target tissue.23. The drug delivery method of claim 22, wherein the drug comprises atleast one of: a chemotherapeutic treatment; a monoclonal antibody (mAB);a ferritin; or a ferumoxytol.
 24. A therapy formulation comprising: aheat substrate agent configured to be hardened at and fixed to anin-vivo target site when subjected to externally applied heat toincrease the temperature of the heat substrate agent; and a polymerconfigured to contain a therapy drug agent, the polymer configured toexpel the therapy drug agent at the target site after its temperatureincreases to deliver the therapy drug over an extended time, the heatsubstrate agent and polymer forming a combination therapy formulationformulated for direct delivery to target tissue at the target site; thecombination therapy formulation being formulated so that a simultaneousincrease in the temperature of the therapy drug, heat substrate agentand polymer is substantially uniformly beyond a given temperature. 25.The therapy formulation of claim 24, wherein the combination therapyformulation comprises the therapy drug agent.
 26. The therapyformulation of claim 24, wherein the heat substrate agent is a materialimageable by x-ray CT.
 27. The therapy formulation of claim 24, whereinthe polymer comprises a reverse phase change polymer.
 28. The therapyformulation of claim 24, wherein the externally applied heat is appliedby a microwave energy source or an electromagnetic energy source. 29.The therapy formulation of claim 28, wherein the heat substrate agentenhances the temperature increase of the therapy drug, heat substrateagent and polymer upon application of the externally applied heat by themicrowave energy source or electromagnetic energy source.
 30. Thetherapy formulation of claim 24, wherein the polymer is a hydrogel. 31.The therapy formulation of claim 24, wherein the heat substrate agent isa thermal accelerant.
 32. The therapy formulation of claim 24, whereinthe heat substrate agent comprises at least one of: engineered ferritin;ferumoxitol; CsCl; or CsI.